Chemokine receptor CCR7 regulates the intestinal TH1/TH17/Treg balance during Crohnˈs-like murine ileitis

EN McNamee, JC Masterson, M Veny… - Journal of Leucocyte …, 2015 - academic.oup.com
EN McNamee, JC Masterson, M Veny, CB Collins, P Jedlicka, FR Byrne, GY Ng…
Journal of Leucocyte Biology, 2015academic.oup.com
The regulation of T cell and DC retention and lymphatic egress within and from the intestine
is critical for intestinal immunosurveillance; however, the cellular processes that orchestrate
this balance during IBD remain poorly defined. With the use of a mouse model of TNF-driven
Crohnˈs-like ileitis (TNF Δ ARE), we examined the role of CCR7 in the control of intestinal T
cell and DC retention/egress during experimental CD. We observed that the frequency of
CCR7-expressing TH1/TH17 effector lymphocytes increased during active disease in TNF Δ …
Abstract
The regulation of T cell and DC retention and lymphatic egress within and from the intestine is critical for intestinal immunosurveillance; however, the cellular processes that orchestrate this balance during IBD remain poorly defined. With the use of a mouse model of TNF-driven Crohnˈs-like ileitis (TNFΔARE), we examined the role of CCR7 in the control of intestinal T cell and DC retention/egress during experimental CD. We observed that the frequency of CCR7-expressing TH1/TH17 effector lymphocytes increased during active disease in TNFΔARE mice and that ΔARE/CCR7−/− mice developed exacerbated ileitis and multiorgan inflammation, with a marked polarization and ileal retention of TH1 effector CD4+ T cells. Furthermore, adoptive transfer of ΔARE/CCR7−/− effector CD4+ into lymphopenic hosts resulted in ileo-colitis, whereas those transferred with ΔARE/CCR7+/+ CD4+ T cells developed ileitis. ΔARE/CCR7−/− mice had an acellular draining MLN, decreased CD103+ DC, and decreased expression of RALDH enzymes and of CD4+CD25+FoxP3+ Tregs. Lastly, a mAb against CCR7 exacerbated ileitis in TNFΔARE mice, phenocopying the effects of congenital CCR7 deficiency. Our data underscore a critical role for the lymphoid chemokine receptor CCR7 in orchestrating immune cell traffic and TH1 versus TH17 bias during chronic murine ileitis.
Oxford University Press